P365: INCORPORATION OF NELARABINE (NEL), PEGYLATED ASPARAGINASE (PEG) AND VENETOCLAX (VEN) IN THE FRONTLINE THERAPY OF ADULT PATIENTS WITH T-ACUTE LYMPHOBLASTIC LEUKEMIA/T-LYMPHOBLASTIC LYMPHOMA (T-ALL/LBL)
Authors: F. Ravandi, E. Jabbour, N. Jain, T. Kadia, B. Gautam, M. Konopleva, W. Wierda, J. Burger, G. Issa, A. Maiti, H. Balkin, M. Kelly, R. Garris, P. Kebriaei, A. Ferrajoli, G. Garcia-Manero, Y. Alvarado, N. Short, H. Kantarjian
Journal: HemaSphere (2022)

Background: NEL is effective for patients (pts) with relapsed T-ALL/LBL but its incorporation into the front-line therapy has not been investigated. In children, addition of NEL to the induction regimen improved disease-free survival (DFS) but not overall survival (OS) (Dunsmore KP, JCO, 2020). VEN has shown preclinical and clinical activity in relapsed T-ALL/LBL. Aims: We investigated addition of NEL and PEG into the hyperCVAD (HCVAD) regimen in adult pts with T-ALL/LBL. We then explored the safety and efficacy of addition of VEN to this regimen. Methods: Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles of HCVAD (cycles 1,3, 5, 7) alternating with high dose ara-C and methotrexate (MTX) (cycles 2, 4, 6, 8) at approximately 3 weeks intervals. 2 cycles of NEL (650 mg/m% daily x 5) were initially administered after the 8 cycles (cohort 1) but later moved to after cycle 4 (cohort 2) and then PEG (1500 IU/m2 capped at 3750 IU) was added on day 5 of NEL cycles (cohort 3). More recently, VEN 400 mg daily on the first 7 days of each of 8 cycles of therapy was added (cohort 4) and this was later adjusted to be given for 7 days on the induction cycle and reduced to 3 days per cycle in pts with ETP-ALL or with persistent MRD with no VEN after cycle 1 in all other pts (cohort 5) Pts with ETP-ALL were referred for allogeneic stem cell transplant in CR. After the completion of the intensive phase, all pts in all cohorts received 30 cycles of maintenance with monthly POMP and early intensification with NEL/PEG on cycles 6 and 7 and late intensification with MTX/PEG in cycle 18 and HCVAD on cycle 19. All pts received 8 intrathecal doses of MTX alternating with ara-C and mediastinal radiation was considered in pts with balky mediastinal disease. Results: Between 8/2007 and 12/2021. 120 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=8)(Table). 74 pts had T-ALL, 45 T-LBL and 1 biphenotypic T/myeloid leukemia. Median age was 35 yrs (range 18-78), 93 pts were male (78%) and 106 pts (88%) had PS 0-1. In pts with T-ALL, median bone marrow blast % was 81% (range, 20-97%). 6 pts (5%) had CNS disease. Cytogenetics was diploid in 77 pts (64%), abnormal in 34 (28%), and unavailable in 9 pts (7.5%). Pts were further characterized as thymic (n=53), early T-cell precursor (ETP; n=23), near ETP (N=19) mature (n=11), not otherwise specified (NOS; n=11), and early-non-ETP (n=3). 25 pts had received 1-2 prior cycles of therapy prior to enrollment with 18 having achieved CR. 30-day mortality was 0%. 106 pts (88%) had ≥ one grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 92 pts (77%) and elevated liver enzymes in 25 pts (21%). Overall response rate (CR/CRi/PR) was 97% with CR/CRp in 95/102 pts (93%), PR in 4 (4%), and no response in 3 (3%). The median no. of cycles to response (including negative PET scans) was 1 (range 1-10). CR/CRp rate in T-ALL was 88% and T-LBL was 100%. At a median follow-up of 48 months (mo; 2-168), 79 pts (66%) are alive with a median PFS and OS of 135 and 135 mo (Figure) and 73 pts (61%) remain in CR. Image:Summary/Conclusion: Addition of NEL/PEG cycles to the HCVAD regimen is feasible and may be beneficial. Addition of VEN to each cycle is associated with significant myelosuppression. Lower doses of VEN may benefit selected pts.